Combinations of vasoprotective agents and formulations containing them

ABSTRACT

Combinations of vasoprotective agents useful for the prevention and the treatment of vascular injuries induced by an excess of plasma lipids comprising polycosanols, tocotriends and/or lycopene, procyanidole oligomers and vegetable oil rich in insaturated fatty acids.

FIELD OF THE INVENTION

The present invention relates to combinations of vasoprotective agents useful for the prevention and the treatment of vascular injuries induced by an excess of plasma lipids.

The combinations of the invention reduce blood cholesterol and triglyceride levels while protecting the vascular wall against the injuries induced by overproduction of free radicals and cholesterol oxidized forms, thus strengthening the wall.

DISCLOSURE OF THE INVENTION

The present invention relates to combinations of vasoprotective agents and compositions comprising said combinations.

The arteriosclerotic disease is a very complex phenomenon not only connected with lipid conditions, therefore any synergetic actions concerning vascular protection and reduction of free radicals overproduction have large therapeutic interest. Chronic degenerative diseases such as cardiovascular diseases do not have a single origin. High trigyceride and cholesterol levels, accompanied by altered ratios of the lipoprotein fractions, as well as hypertension, undoubtedly induce marked vascular injuries with unfavourable prognosis. There is therefore the need to decrease blood cholesterol and trigycerides levels, while strengthening and protecting the arterial walls.

It has now been found that this objective can advantageously be attained by combining vasoprotective agents having different mechanisms of action.

The invention relates in particular to pharmaceutical, dietetic or nutritional compositions comprising:

one or more polycosanols or esters thereof, either pure or as extracts;

ocotrienol and/or lycopene, preferably tocotrienol;

one or more procyanidole oligomers optionally complexed with phospholipids;

a vegetable oil rich in ω-3, ω-6 unsaturated fatty acids.

The hypocholesterolemizing, or more generally anti-atherosclerotic, activity of each single component of the combination is known, but only through the combined use thereof particularly remarkable preventive or therapeutic effects can be attained.

The use and the preparation of procyanidole oligomers complexed with phospholipids as anti-atherosclerotic agents are disclosed in WO 99/29331.

Polycosanols, as well as ω-3, ω-6 unsaturated fatty acids, have been the object of investigations in the cardiologic and cardio-vascular fields for some time (Int J Clin Pharm Res 1994; 14:27-33 and Ann. Intern. Med. 1999; 130:554-62, respectively) while tocotrienol and lycopene, belonging to the family of carotenoids, have been extensively studied as agents able to prevent lipoperoxidation and formation of free radicals, and also as chemo-preventive agents (Clin. Biochem 1999; 32:309-19).

The polycosanols used according to the invention are straight, long chain aliphatic alcohols, typically straight alcohols having 24 to 30 carbon atoms, obtainable by saponification of waxes from vegetable materials such as olive, wheat, rice, sugar cane and other sources. These compounds can be used either in the free form or esterified with ferulic acid or other cinnamates variously substituted at the phenyl moiety, such as p-NO₂, p-OH, and m-Cl cinnamates.

The procyanidole oligomers for use according to the invention can be obtained from Vitis vinifera, Camellia sinensis, Aesculus hippocastanum, Olea europea.

The vegetable oil is preferably selected from Enothera biennis, Ribes nigrum or Portulaca oleracea oils, more preferably Enothera biennis oil. The ω-3, ω-6 unsaturated fatty acids present in said oils can optionally be transformed into the corresponding alkyl esters, in particular the corresponding ethyl esters, by transesterification, for example by treating the oil with ethanol and H₂SO₄ in the presence of benzene to azeotropically remove water.

The compositions of the invention can further contain luteolin per se or in the form of 7,3′,4′-hydroxyethyl derivatives.

The formulations of the invention can contain 5 to 30 mg, preferably 15 mg, of polycosanols; 1 to 50 mg, preferably 8 mg, of tocotrienol or lycopene; 30 to 200 mg of proanthocyanidins or 100 to 320 mg of proanthocyanidins complexed with phospholipids, and 150 to 300 mg of vegetable oils, per unit dosage form.

20 Patients suffering from essential hyperlipidemia with carotid plaques were treated with a formulation of the invention having the following composition:

Rice polycosanols (70% polycosanols) 15 mg Tocotrienol 14 mg Procyanidole oligomers/phospholipids 320 mg Enothera biennis oil q.s. to 500 mg

After two month treatment with two capsules/day, patients showed normalized lipid parametres and improved conditions of the plaques, as evidenced by EcoDoppler.

The following examples illustrate the invention in greater detail:

EXAMPLE I

Polycosanols from rice or olive residues oils 15 mg Tocotrienol 14 mg Procyanidole oligomers/phospholipids 320 mg Enothera biennis oil q.s. to 500 mg

EXAMPLE II

Polycosanols from olive residues oil 30 mg esterified with ferulic acid Tocotrienol 14 mg Procyanidole oligomers/phospholipids 250 mg Enothera biennis oil q.s. to 500 mg

EXAMPLE III

Octacosanyl ferulate 12 mg Tocotrienol 12 mg Epigallocatechin gallate/ 250 mg phosphatidyl choline1:1 Ethyl eicosapentanoate q.s. to 500 mg

EXAMPLE IV

Polycosanols from rice or olive residues oils 15 mg esterified with ferulic acid Tocotrienol 14 mg Procyanidole oligomers/phospholipids 250 mg Enothera biennis oil q.s. to 500 mg

EXAMPLE V

Polycosanols from rice or olive residues oils 15 mg Tocotrienol 14 mg Procyanidole oligomers 150 mg Enothera biennis oil q.s. to 500 mg 

1. Pharmaceutical, dietetic or nutritional compositions comprising: one or more polycosanols or esters thereof, either pure or as extracts; tocotrienol and/or lycopene, preferably tocotrienol; one or more procyanidole oligomers optionally complexed with phospholipids; a vegetable oil rich in ω-3, ω-6 unsaturated fatty acids.
 2. Compositions as claimed in claim 1, in which the vegetable oil is selected from Enothera biennis, Ribes nigrum or Portulaca oleracea oil.
 3. Compositions as claimed in claim 2 in which the vegetable oil is Enothera biennis oil.
 4. Compositions as claimed in claim 1, further containing luteolin either per se or in the form of 7,3′, 4′-hydroxyethyl derivatives.
 5. Compositions as claimed in claim 1 in which polycosanols are esterified with ferulic acid or other variously substituted cinnamates.
 6. Compositions as claimed in claim 1 in which procyanidole oligomers derive from Vitis vinifera, Camellia sinesis, Aesculus hippocastanum, Olea europa.
 7. Compositions as claimed in claim 1, comprising 5 to 30 mg of polycosanols, 1 to 50 mg of tocotrienol or lycopene, 100 to 320 mg of proanthocyanidins complexed with phospholipids, 150 to 300 mg of vegetable oil, per unitary dosage form.
 8. Method for the preparation of hypocholesterolemizing and/or anti-atherosclerotic pharmaceutical, dietetic or nutritional compositions, which comprises using a combination of an effective amount of: one or more polycosanols, in the free or esterified form, either pure or extracts containing them; tocotrienol and/or lycopene, preferably tocotrienol one or more procyanidole oligomers optionally complexed with phospholipids; a vegetable oil rich in ω-3, ω-6 unsaturated fatty acids.
 9. Compositions as claimed in claim 2, further containing luteolin either per se or in the form of 7,3′, 4′-hydroxyethyl derivatives.
 10. Compositions as claimed in claim 3, further containing luteolin either per se or in the form of 7,3′, 4′-hydroxyethyl derivatives.
 11. Compositions as claimed in claim 2, comprising 5 to 30 mg of polycosanols, 1 to 50 mg of tocotrienol or lycopene, 100 to 320 mg of proanthocyanidins complexed with phospholipids, 150 to 300 mg of vegetable oil, per unitary dosage form.
 12. Compositions as claimed in claim 3, comprising 5 to 30 mg of polycosanols, 1 to 50 mg of tocotrienol or lycopene, 100 to 320 mg of proanthocyanidins complexed with phospholipids, 150 to 300 mg of vegetable oil, per unitary dosage form.
 13. Compositions as claimed in claim 4, comprising 5 to 30 mg of polycosanols, 1 to 50 mg of tocotrienol or lycopene, 100 to 320 mg of proanthocyanidins complexed with phospholipids, 150 to 300 mg of vegetable oil, per unitary dosage form.
 14. Compositions as claimed in claim 5, comprising 5 to 30 mg of polycosanols, 1 to 50 mg of tocotrienol or lycopene, 100 to 320 mg of proanthocyanidins complexed with phospholipids, 150 to 300 mg of vegetable oil, per unitary dosage form.
 15. Compositions as claimed in claim 6, comprising 5 to 30 mg of polycosanols, 1 to 50 mg of tocotrienol or lycopene, 100 to 320 mg of proanthocyanidins complexed with phospholipids, 150 to 300 mg of vegetable oil, per unitary dosage form. 